Project Summary/Abstract: Research: Type 1 Diabetes (T1D) is an autoimmune disease characterized by loss of insulin-producing islet ?- cells and insulin deficiency. Despite several clinical trials no intervention has been found yet which has long- term effects, and can be utilized safely over years without adverse effects. Therefore, developing therapeutic targets which are safe, and act directly on islets to attenuate inflammatory responses and improve ?-cell function in humans with T1D are of utmost importance. We recently discovered a novel class of mammalian lipids called Palmitic Acid Hydroxy Stearic Acids (PAHSAs) that are highly anti-inflammatory and anti-diabetic. PAHSAs also potently reduce the incidence of T1D in non obese diabetes (NOD) mice, a model of autoimmune T1D. This project will investigate the mechanisms for these beneficial effects of PAHSAs in T1D. Specific Aim1: To determine the immune mechanisms by which PAHSAs delay onset and reduce incidence of T1D. Specific Aim2: To investigate the cellular mechanisms by which PAHSAs directly promote ?-cell survival and function. This research will provide novel insights into how PAHSAs modulate immune function and promote islet ?-cell survival/function which may be used develop novel therapies for T1D treatment in humans. Candidate: I have a long-standing interest in studying the signaling mechanisms responsible for islet ?-cell death and dysfunction. My doctoral training with Dr. Anjan Kowluru focused on the role of small G-proteins and reactive oxygen species in insulin secretion under physiological and pathophysiological states. My postdoctoral training with Dr. Barbara B Kahn has been geared towards identifying novel therapeutic approaches to enhance ?-cell function and improve glucose-insulin homeostasis. My tenure in Dr. Kahn?s lab has been extremely productive and I have authored and co-authored 8 papers with one first author paper in Cell, a second in under revision at Cell Metabolism. During the grant period, I will expand my knowledge of islet autoimmunity by learning immunological techniques and signaling pathways involved in ?-cell survival/function. This K01 career development award will provide me with protected research time to undergo the final and critical training phase of my career prior which will equip me to successfully transition to independence. Environment: The Division of Endocrinology, Metabolism and Diabetes at the BIDMC is an ideal training site for basic scientists and has a distinguished record of training young scientists towards a path of independence. Graduates from Division have gone on to make transformative discoveries that continue to shape the future of diabetes and metabolism research. The research proposed in this award will be carried under the mentorship of Dr. Kahn at BIDMC and Dr. Mathis at the HMS with guidance of a scientific advisory committee (Drs. Hao Wu, Gokhan Hotamisligil, and Susan Bonner-Weir) who are committed to my development as an independent scientist. I will meet weekly with Dr. Kahn, monthly with Dr. Mathis, and quarterly with Advisory Committee members to discuss results, experimental design, future directions, and for the preparation of my R01 grant.